This invention concerns a process for making certain anti-inflammatory compounds. In particular, the application concerns a process for making compounds of formula I as disclosed hereunder, which compounds are potent cyclooxygenase-2 inhibitors.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormnones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
WO 96/24585 published Aug. 15, 1996 and WO 96/10012, published Apr. 4, 1996 disclose methods of making 2-aryl-3-aryl-pyridines. In the invention disclosed herein, 2-aryl-3-aryl-pyridines are prepared in a simple to conduct, 1 step condensation from readily available starting materials. It is, therefore, surprisingly convenient and more efficient than the previously described procedure, in which the 2-aryl-3-aryl pyridine was constructed by serial stepwise addition of the aryl groups to the central pyridine ring. Moreover, the process of the instant invention is surprisingly superior in that expensive palladium reagents are not required, and the cumbersome protection/de-protection sequence of the prior art process is avoided.
The preparation of 2-chloromalondialdehyde was first accomplished by Diekmann in 1904 (W. Dieckmann, L. Platz, Ber. Deut. Chem. Ges. 1904, 37, 4638). The chemistry of 2-halomalondialdehydes was thoroughly reviewed in 1975 (C. Reichardt and K. Halbritter, Angew. Chem. Int. Ed. 1975, 14, 86). This review does not mention a pyridine synthesis using these reagents. The only recorded use of 2-chloromalondialdehyde for the preparation of a pyridine is in a recent patent application (F. J. Urban, U.S. Pat. No. 5,206,367 to Pfizer and Brackeen, M. and Howard, H. R. European Patent Application number 89307339.5 (EP 0 352 959) to Pfizer), where chloromalondialdehyde is first converted to 2,3-dichloroacrolein, which is subsequently condensed with the enamine derived from 1,3-cyclohexanedione to give the annulated pyridine in 28% yield.
A recent comprehensive review of pyridine synthesis and reactivity (D. Spitzner in Methoden der Organischen Chemie (Houben-Weyl), pages 286 to 686, Vol. E 7b, Editor R. P. Kreher, 1992, Georg Thieme Verlag) gives no examples for the use of halomalondialdehydes for the pyridine synthesis. Nitromalondialdehyde has been condensed with ethyl-2-amino-crotonate to give the 5-nitropyridine, albeit in lower yield (35-50%) (J. M. Hoffman et.al. J. Org. Chem. 1984, 49, 193 and P. E. Fanta, J. Am. Chem. Soc. 1953, 75, 737). The use of ethoxycarbonyl malondialdehyde derivatives leads to 5-ethoxycarbonyl pyridines (S. Torii et. al. Synthesis, 1986, 400).